Abstract
Cyclodextrins (CDs) were first isolated in 1891 as degradation products of starch from a medium of Bacillus amylobacter. They are cyclic water-soluble, nonreducing, macrocycle carbohydrate polymers constructed from α-(1-4)-linked d-glucopyranose units (naturally occurring α, β, and γ formed by 6, 7, and 8 glucose units), in a ring formation and present a toroidal, hollow, truncated cone shape. Their most important property is the ability to establish specific interactions – molecular encapsulation – with various types of molecules through the formation of non-covalently bonded entities, either in the solid phase or in aqueous solution, taking up a whole molecule, or some part of it, into their cavities. This process in part mimics the “lock and key” mechanism of enzyme catalysis. Complexation may cause changes in physicochemical properties of the guest molecule (e.g., solubility, stability, kinetics and bioavailability, toxicity). Their negligible cytotoxic effects promoted them to the GRAS list and led them to be widely used in many industrial products and technologies.
Access provided by Autonomous University of Puebla. Download reference work entry PDF
Similar content being viewed by others
Keywords
- Cyclodextrin
- Cyclodextrin derivatives
- Complex formation
- Molecular encapsulation
- Applications
- Toxicity
- Pharmacokinetics
1 Introduction
1.1 Historical Background
Since the beginning of times, the most important discoveries happen as casual observation due to researchers’ curiosity (Table 1). Cyclodextrin (CD) discovery also followed this pattern as they were first isolated in 1891 by Villiers when, in addition to reducing dextrins, beautiful crystals were observed in alcohol waste as degradation products of starch from a medium of Bacillus amylobacter. These substances were called “cellulosine” due to its similarity to cellulose (Villiers 1891). In the following years (early twentieth century), another prominent scientist, Schardinger, made important discoveries for CDs’ science. In 1903, this author was responsible for the isolation of two crystalline products showing lack of reducing properties: dextrins A and B. In 1904, Schardinger isolated a new organism capable of producing acetone and ethyl alcohol from sugar- and starch-containing plant material (Eastburn and Tao 1994). In 1911, he described that the strain Bacillus macerans produces large amounts of crystalline dextrins (25–30 %) from starch. Thus, Schardinger is considered the founder of CD chemistry due to his work to characterize Villiers’ “cellulosines” from 1903 to 1911, determining that they were cyclic oligosaccharides (Schardinger 1903a, b, 1904, 1911; Szejtli 1998). It is for this reason that CDs are also termed Schardinger dextrins, especially in the older literature. Since then several fractionation schemes for the production of CDs were also developed (Stella and Rajewski 1997; Matsuda and Arima 1999; Mabuchi and Ngoa 2001). The γ-dextrin was only isolated in 1935.
Pure CDs (i.e., cyclic water-soluble, nonreducing, macrocycle polymers) were prepared in the early part of the last century by Freudenberg and co-workers (Freudenberg and Meyer-Delius 1938; Freudenberg et al. 1947), who reported that CDs are constructed from α-(1-4)-linked d-glucopyranose units, in a ring formation (Saenger 1980; Uekama 1981; Szejtli 1982). In 1948, using X-ray crystallography the γ-CD structure was clarified. Immediately after, the most important property of CDs was recognized: their ability to form inclusion complexes. The general title for this class of complexes, “inclusion compounds” (“einschlussverbindung”), was first used by Schlenk in 1949. Besides the general terms (“occlusion” and “adducts”), other terms that have been used to describe these complexes are “molecular compounds,” “cryptates” (Frank 1975; Szejtli 1982), and “clathrates” (Powell 1948). The term “clathrate,” derived from the Latin “clathratus,” meaning “enclosed or protected by cross bars of a grating,” has been used to describe the cage-like structure of the hydroquinone inclusion compounds.
Although Chemical Abstracts and several other reference sources use the term “clathrates” as a general descriptor for inclusion compounds, this term more appropriately describes only cage-like polymolecular inclusion compounds (Cabral-Marques 1994a). In 1961 the existence of larger natural CDs, namely, δ- (delta), ε- (epsilon), ζ- (zeta), and η- (nu) CD, was proved (9–12 glucose residues) (Hirose and Yamamoto 2001). CD chemistry was discussed in detail by Bender and Komiyama (Bender and Komiyama 1978).
1.2 Occurrence/Sources
Although discovered more than 100 years ago as previously referred, the cyclic glucooligosaccharides termed CDs (based on dextrose, which is an old name for glucose) remained laboratory curiosities until the 1970s when they began to be used commercially (Szejtli 1998). Its production results from degrading the starch by the enzyme cyclodextrin glucanotransferase (CGTases), involving excision and reconnection of single turns from the helical α-(1→4)-glucan (amylose) chain (Fig. 1) to provide cyclic α-(1→4)-linked glucooligosaccharides with six (α-CD), seven (β-CD), and eight glucose units (γ-CD) (Rendleman 1999; Lichtenthaler 2010). This intramolecular transglycosylation is called cyclization reaction (Szejtli 1998; Cheirsilp et al. 2010).
The starch sources used to produce CDs are varied and include according to different authors the following substrates:
-
Liquefied starch, maltodextrin, or long-chain maltooligosaccharides (Rendleman 1999)
-
Maltodextrin and commercial soluble starch, corn, cassava, sweet potato, and waxy corn starches (Alves-Prado et al. 2008)
-
Amaranth starch (Urban et al. 2012)
-
Soluble and cocoyam starch (Mora et al. 2012)
-
Starch such as potato, tapioca, and corn (Shahrazi et al. 2013)
CGTase is specifically active on both structures of amylose and amylopectin (Shahrazi et al. 2013). Several microorganisms and methods have been used to produce or use CGTase as described in the following:
-
Bacillus amylobacter in 1881 (Szejtli 1998).
-
Bacillus macerans (Rendleman 1999).
-
Bacillus circulans DF 9R (Rosso et al. 2002).
-
Bacillus clausii strain E16 (Alves-Prado et al. 2008).
-
Bacillus megaterium (Zhekova and Stanchev 2011; Sivakumar and Shakilabanu 2013).
-
Alkaliphilic Bacillus licheniformis (Thombre and Kanekar 2013).
-
CGTase was anchored on the surface of Saccharomyces cerevisiae and was used as an immobilized enzyme (Wang et al. 2006).
-
Escherichia coli pAD26 cells immobilized on cotton (Kriaa et al. 2012).
-
Amphibacillus sp. NPST-10 (Ibrahim et al. 2012).
-
Paenibacillus macerans CCM 2012 (Urban et al. 2012).
-
Amphibacillus sp. NRC-WN (Al-Sharawi et al. 2013).
2 Structure and Properties
2.1 Parent Cyclodextrins
The most common of these naturally occurring, ring-shaped molecules are the α- (alpha), β- (beta), and γ- (gamma) CDs formed by six, seven, and eight glucose units (Fig. 2) and cavities’ diameters smaller than 0.6, 0.8, and 1.0 nm, respectively (Frank 1975; Szejtli 1982). Because of their sugar backbone, these CDs are also known as cycloamyloses: hexa- (C6A), hepta- (C7A), and octa-amylose (C8A) (Szejtli 1982) or cyclohexa-, cyclohepta-, and cyclooctaglucan and α-, β-, and γ-amylosan (French 1957).
CDs have no well-defined melting point and start to decompose at temperatures above 270 °C, and at 300 °C a sharp endothermic process is detected, which indicates that the melting is accompanied by decomposition (Szejtli 1982). Generally their solubility in water is greatly increased at higher temperatures (except for the dimethyl-β-CD which decreases). The most important characteristics of the natural CDs are summarized in Table 2 (Saenger 1980; Szejtli1998; Pitha et al. 1983; Duchêne et al. 1986; Bas and Rysanek 1987; Uekama and Otagiri 1987; Duchêne and Wouessidjewe 1990a; Salústio et al. 2011).
It is noteworthy that there are differences in the reported central cavity and outer periphery diameters of the CDs. Molecule CDs present a hydrophilic exterior, which can dissolve in water, and an apolar cavity, which provides a hydrophobic matrix, described as a “micro heterogeneous environment” (Szejtli 1989).
Nuclear magnetic resonance (NMR) and X-ray diffraction indicate the C-1 chair conformation for the glucose molecule (Rao and Foster 1963). CDs are shown to have a toroidal, hollow, truncated cone structure, where the secondary OH groups on the C-2 and C-3 atoms are located on the wider side of the torus, while the primary OH groups on the C-6 are positioned on the opposite side of the torus (the narrower) and are directed “away” from the cavity except if H-bonded to include guest molecules (Saenger 1982; Szejtli 1988). The CH groups comprising H-1, H-2, and H-4 are located on the exterior of the molecule, while the polar sugar OH groups are oriented to the cone exterior, and as a consequence the external faces of CDs are hydrophilic leading to their aqueous solubility. The interior of the torus offers an environment of much lower polarity than is present in water, so it can be considered as a “hydrophobic cavity,” which is lined by two rings of CH groups (H-3 and H-5), and by a ring of glucosidic oxygen-bridge atoms “ether oxygens” (O-4 and O-5) (Saenger 1982; Jones et al. 1984; Uekama and Otagiri 1987), H-6 forms the narrower rim of the truncated cone. The result of this amphipathic property is that CDs can form soluble, reversible inclusion complexes with water-insoluble compounds resulting in compound solubilization.
In all CD crystal structures, H-bonding between adjacent glucoses is found, with O-3....H-O-2 distances in the usually accepted range, 0.28–0.31 nm. H-bonding between these secondary OH groups appears to be preferred because their pKa, around 12.2 (Chin et al. 1968), is relatively low, suggesting enhanced polarization and therefore good H-bond donor and acceptor functions. This ring of H-bonds is, in general, fully established in β- and γ-CDs, but in α-CD, the curvature of the ring produces, on average, longer O-3....H-O-2′ separations, and H-bonding is weaker and can break down, as shown for the “empty” hexahydrate where four O-3....H-O-2′ hydrogen bonds are formed but two are broken. Spectroscopic data also indicate that β-CD is rigid in aqueous solution, whereas α-CD is flexible and undergoes conformational change if inclusion of a guest molecule occurs, as proposed in the “induced-fit” concept for proteins (Saenger 1982; Szejtli 1988). These interactions prevent hydration by water molecules (Szejtli 1985; Uekama and Otagiri 1987) resulting in poor aqueous solubility. In order to improve CDs’ aqueous solubility, their structure has been modified via alkylation and hydroxyalkylation (Uekama and Otagiri 1987; Yoshida et al. 1988; Jicsinszky 2014).
The OH groups on C-2, C-3, and C-6 are available as points of structural modification without danger of eliminating the “central void” (MacNicol et al. 1978). The OH groups on C-6 are the most reactive, whereas the OH at C-3 are much less reactive than those at C-2.
2.2 Large Cyclodextrins
CDs with fewer than six glucopyranose residues do not exist, probably for steric reasons (Duchêne and Wouessidjewe 1990b). The existence of CDs comprising more than 8 glycosyl units was referenced in 1948 by Freudenberg and Cramer (Freudenberg and Cramer 1948). A decade later these findings were subsequently substantiated by French and co-workers, who reported the isolation and partial characterization of large CDs with 9, 10, 11, and 12 glycosyl units in the macrocycle. However, some doubts remained concerning these CDs since they were not able to experimentally distinguish the large CDs from branched CDs (Pulley and French 1961; French et al. 1965; Szejtli 1988). During last decades, the existence of the large CDs has been fully proven. CDs containing up to 31 glycosyl units have been purified and characterized (Koizumi et al. 1999), and the existence of even larger CDs with degrees of polymerization up to several hundreds of glycosyl units has been reported (Kitamura 2000; Larsen 2002). Indeed, large CDs are not commercially exploited due to their extremely small isolation/purification yields and lack of their complexing properties (French 1957; Pulley and French 1961; French et al. 1965; Szejtli 1982).
Large CDs (Table 3) have often been designated “cycloamylose” (abbreviated CDn, where n designates the number of glucose molecules in the macrocycle) (Kitamura 2000; Larsen 2002).
2.3 Cyclodextrins Derivatives
In order to improve the physicochemical properties (i.e., better solubility, stability, and inclusion formation abilities/release behaviors of the substrate molecules) of the natural CDs, many derivatives were synthesized by various molecular manipulations (Frömming 1987; Frömming et al. 1987).
These derivatives (Table 4) usually are produced by alkylations, aminations, esterifications, or etherifications of their primary and secondary OH groups, leading also to the formation of polymeric and amphiphilic CDs (long alkyl or fluoroalkyl chains at primary and/or secondary sides of the CDs) (Bender and Komiyama 1978; Szejtli 1982; Szente et al. 1999; Sollogoub 2013). Croft and Bartsch (1983) published an interesting review of chemical methods for modifying CDs.
3 Complexation
3.1 Complexes Formation
CDs are able to form inclusion complexes with a wide variety of hydrophobic guest molecules. Thus, guest molecules can be totally or partially entrapped into CDs’ cavities and in several molar ratios. The complexation process (Fig. 3) involves the insertion of the less polar part of the guest molecule into the host cavity, while the more polar and often charged group of the guest is exposed to the bulk solvent. During insertion phenomenon the water molecules are removed from the inside of CD cavity due to their thermodynamical instability. The inclusion complex formation is achieved by weak interactions such as van der Waals, hydrogen bonding, and hydrophobic effect, among others (Szejtli 1982; Cabral-Marques 1994a; Rekharsky and Inoue 1998; Sun et al. 2006). This process does not occur by means of ionic, covalent, or coordinate covalent bonds (Frank 1975; Cramer 1982; Charoenchaitrakool et al. 2002). The specific association of two molecules results not by a single weak interaction but through the simultaneous cooperation of several weak interactions. Molecular mechanics calculations have also been made to investigate the solute-solvent interactions between CD and water and the molecular interactions in inclusion complexes of CDs. The essential criterion is simply that the enclosed molecule or guest must be of a suitable size and shape (i.e., the best possible filling of space) to fit into a cavity within a solid structure formed by host molecules (Powell 1948, 1954). The main binding contribution between CD and its partners is the geometrical fitting, so complexation occurs in a stereo-specific manner (Cramer 1982). The spatial requirements for the formation of a CD inclusion compound in part mimic the enzyme catalysis “lock-key” mechanism which occurs if the substrate/guest molecule is orientated properly with respect to the active centers of the host (Cramer and Hettler 1967). It is also possible to use the CD to block some reactive sites on the guest and expose others.
CD complex formation, from a pharmaceutical point of view, is equivalent to molecular encapsulation , as the drug molecules are isolated from each other and are dispersed on a molecular level in an oligosaccharide matrix, i.e., a process similar to drug encapsulation in a hydrophilic matrix (e.g., polyvinylpyrrolidine or cellulose) (Pitha et al. 1983; Szejtli 1985).
Inclusion complexes can be obtained by several techniques, such as physical mixing (Menezes et al. 2012), coprecipitation (Sapkal et al. 2007;Nieddu et al. 2014), complexation in a slurry (Fages et al. 2007; Menezes et al. 2012, 2014), complexation in paste (Gil et al. 2004; Menezes et al. 2012, 2014), extrusion (Yano and Kleinebudde 2010), dry mixing (Higashi et al. 2009), solution/suspension with solvents removal by drying methods (spray-drying, freeze-drying) (Salústio et al. 2009), sealed-heating method (Nieddu et al. 2014), and supercritical fluids (Junco et al. 2002). In order to enhance the complex efficiency of the CDs, different methods can be used such as ionization of the drug, salt formation, formation of metal complexes, addition of organic cosolvents to the aqueous complexation media, and the use of supercritical fluids, since all promote an intrinsic solubility enhancement of the drug-favoring complexation (Junco et al. 2002; Loftsson and Duchêne 2007). There are also references to the inclusion of essential oils (EO) into β-CD through a sol-gel process, which consists in the introduction of the suspension containing the EO and β-CD into a colloidal silica, under continuous stirring, at room temperature. This procedure was used to encapsulate mint and lavender oils, which according to the authors, allowed the EOs to be much more protected against the humidity, temperature, and solar light, among other factors (Răileanu et al. 2013).
3.2 Phase Solubility Studies
Phase solubility studies are a traditional approach to determine not only the stability (also called equilibrium) constant value but also to give insight into the stoichiometry of the equilibrium. Experimentally, an excess of a poorly water-soluble guest molecule (e.g., drug, D, representing the substrate) is introduced into several vials to which a constant volume of an aqueous vehicle containing successively larger concentrations of the CD (representing the ligand) is added. Afterwards the vials are shaken at constant temperature until equilibrium is established. The supernatant is spared and the total concentration of the drug (Dt) is determined by a adequate quantification method (e.g., UV-VIS, HPLC, fluorescence). The phase solubility profile is then constructed by assessing the effect of the CD on the apparent solubility of the drug (D) as shown in Fig. 4 (Higuchi and Connors 1965; Brewster and Loftsson 2007; Cabral-Marques 2010). Several behaviors can be identified between two major types: A and B.
Thus, the following profiles may be described as:
-
A-type – formation of soluble inclusion complexes
-
AL-type – linear increase of drug solubility versus CD concentration
-
AP-type – positively deviating from the linear profile (i.e., the solubilization is proportionally more effective at higher concentrations)
-
AN-type – negatively deviating from the linear profile (i.e., the CD is proportionally less effective at higher concentrations)
-
-
B-type – formation of inclusion complexes poorly soluble
-
BS-type – complexes of limited solubility
-
BI-type –formation of insoluble complexes
-
AL profiles indicate a linear increase in solubility in function of CD concentration, and water-soluble complexes are being formed with solubilities higher than that of the uncomplexed substrate. AL-type relationships are first order with respect to the CD and may be of first or higher order with respect to the drug (i.e., D•CD, D 2•CD, D 3•CD, etc.). If the slope of the AL isotherm is higher than the unity, higher-order complexes are assumed to be involved in the solubilization. Although a slope of less than one does not exclude the occurrence of higher-order complexes, a one-to-one complex is often assumed in the absence of other information. AP systems suggest the formation of higher-order complexes with respect to the CD, at higher CD concentrations (i.e., D•CD, D•CD 2, D•CD 3, etc.). The stoichiometry of the formed complexes has historically been implied by the extent of curvature of the phase solubility profile. Thus, when an isotherm best fits to a quadratic function, the formation of a one-to-two (D•CD 2) complex is suggested, one best fits to a cubic function suggests a one-to-three complex (D•CD 3), and so forth. AN profiles have several explanations including bulk changes imparted to the solvent by the CD at various concentrations (i.e., the CD is acting as a chaotrope or kosmotrope or is altering the bulk properties of the media by changing its viscosity, surface tension, or conductivity) and/or CD self-association at high concentrations. Equilibrium constants can be derived from the linear portion of each phase solubility profile, given by Eq. 2. To this point, intrinsic drug solubility is given as Do and the formed complex is represented by D•CD.
The complexation process is most frequently a 1:1 host/guest ratio; however, 2:1, 1:2, or even higher-order associations may exist at the equilibrium, almost always simultaneously. Equilibrium established between dissociated and associated species can be expressed by the stability (association or equilibrium) constant and designed as K s or K a or K 1:1 (Szejtli 1998). These constants may be determined by several methods, e.g., phase solubility studies (Waleczek et al. 2003; Daletos et al. 2008), NMR, UV-VIS, HPLC (Cabral-Marques 1994a, b), TLC (Lederer and Leipzig-Pagani 1996), and static headspace method (Saito et al. 1999). The CD association with the drug (D) or guest molecules and the dissociation of the formed inclusion complexes are governed by a thermodynamic equilibrium showed by the following equations (Szejtli 1998):
and
Then, a dissociation constant can be defined as
Intrinsic drug solubility is given as D 0 and a formed complex is represented by D•CD.
Since
then the values for [D m •CD n ], [D] and [CD] can be derived as
where D 0 is the equilibrium solubility of the drug in the absence of CD, D t is the total concentration of the drug (i.e., the sum of the complexed and uncomplexed forms), and CD t is the total concentration of CD. For equilibria that are first order with respect to the CD (n = 1), the following equation can be obtained:
A plot of D t versus CD t for the formation of D m •CD should, therefore, give a straight line with the y intercept representing D 0 and the slope defined as
Therefore, if m is known, the K can be calculated meaning that for 1:1 complexation, i.e., m = 1, the following graphical approach can be applied:
For 1:1 drug •CD complexes, the complexation efficiency (CE) can be calculated from the slope of the phase solubility diagram according to Eq. 12. When selecting CD or complexation conditions during formulation work, it can frequently be more convenient to compare the CE than K 1:1 values since CE is less sensitive to errors related to estimation of intrinsic drug solubility (Loftsson et al. 2005a):
The CE is the product of the apparent solubility of the poorly soluble drug (D 0) and the apparent stability constant of the complex (K 1:1), assuming formation of 1:1 D•CD. The CE can be increased by either increasing the value of D 0 or the value of K 1:1 or both values simultaneously. This parameter increase can be achieved by the use of drug salts, polymers, and cosolvents. In addition, processing approaches to improve CDs, solubilizing functions should be considered, and formulation concepts such as supersaturation may further help in the optimal use and placement of CD in pharmaceutical dosage forms (Loftsson and Brewster 2012; Ciobanu et al. 2013).
4 Biology/Biotechnological Approaches
4.1 Toxicological Considerations
Due to the importance of CDs and the derivatives, their safety and toxicological profiles have been reviewed by several authors (Cabral-Marques 1994b; Irie and Uekama 1997; Thompson 1997; Del Valle 2003; Stella and He 2008; Arima et al. 2011). As CDs possess MW ranging from almost 1,000 to over 2,000 Da and hydrophilicity (logKo/w −8 to −12) with a significant number of H-donors and acceptors, they are not significantly absorbed from the gastrointestinal tract (GI) in their intact form. Natural CDs and their hydrophilic derivatives present considerable difficulties to permeate lipophilic biological membranes. Even the somewhat lipophilic randomly methylated β-CD does not readily permeate lipophilic membranes, although it interacts more readily with membranes than the hydrophilic CD derivatives (Totterman et al. 1997); for this reason some β-CD derivatives have been considered skin enhancers due to their ability to complex membrane components causing its disruption (Babu and Pandit 2004; Wang et al. 2014). Several CDs, namely, γ-CD, 2-HP-β-CD, SBE-β-CD, sulphated β-CD, and maltosyl β-CD evaluated in a number of safety studies have proven that they appear to be safe even when administered parenterally. However, these same studies proved that the natural α- and β-CDs and the methylated β-CDs are not suitable for parenteral delivery (Del Valle 2003). The α-CD and β-CD, unlike γ-CD, cannot be hydrolyzed by human salivary and pancreatic amylases even if it can be fermented by the intestinal microflora (Irie and Uekama 1997; WHO 2002). One of the target organs where the toxicity profile of several CDs can be assessed is the kidney (Antlsperger and Schmid1996).
4.1.1 α-CD
Oral administration of α-CD is, in general, well tolerated and is not associated with significant adverse effects (Lina and Bär 2004a, b). Only small fractions of α-CD are absorbed intact from the GI tract, and it is mainly excreted unchanged in the urine after IV injection (Table 5) (Brewster and Loftsson 2007). Studies in rats showed that α-CD p.o. was excreted 60 % as CO2 (no CO2 exhalation after p.o. to germ-free rats), 26–33 % as metabolite incorporation, and 7–14 % as metabolites in feces and urine, being mainly excreted in the unchanged form by the renal route after parenteral injection (t 1/2 = 25 min, LD50 oral, rat >10,000 mg/kg, LD50 IV, rat between 500 and 750 mg/kg).
Some other relevant characteristics were observed after this CD administration, such as, skin irritation after IM injection, binding with some lipids, eye irritation, and slight absorption (2–3 %) after oral administration in rats. α-CD is not metabolized in the upper intestinal tract and its cleavage is only due to the intestinal flora of cecum and colon (Del Valle 2003).
4.1.2 β-CD
Due to its low aqueous solubility and side effects (e.g., nephrotoxicity), β-CD is not able to be administered by parenteral route but it can be used in p.o. because by this route is normally nontoxic. However, it must be carefully used because in high doses it may be harmful and therefore not recommended. After p.o. administration, the nontoxic effect level of β-CD was determined to be 0.7–0.8 g/kg/day in rats and about 2/g/kg/day in dogs (Bellringer et al. 1995).
It was noticed that β-CD binds cholesterol, is absorbed in small scale (1–2 %) in the upper intestinal tract after oral administration, and is less irritating than α-CD after IM injection. β-CD is not metabolized in the upper intestinal tract, but suffers bacterial degradation and fermentation in cecum and colon which may lead to gas production and diarrhea (LD50 oral, rat >5,000 mg\kg; LD50 IV, rat = 450–790 mg/kg) (Del Valle 2003). As it will be described in the Regulatory State chapter, β-CD is the most commonly used CD in pharmaceutical formulations, and, thus, it is probably the most studied in humans.
4.1.3 γ-CD
The metabolism of γ-CD closely resembles that of starch and linear dextrins (Munro et al. 2004). Only a small portion of the IV-injected γ-CD is absorbed intact from the GI tract, and it is mostly excreted unchanged in the urine. Oral administration of 8 g γ-CD or 8 g maltodextrin to humans did not reveal any differences in GI tolerance of these two oligosaccharides (Koutsou et al. 1999). The γ-CD showed to promote an insignificant irritation after IM injection and was rapidly and completely degraded by intestinal enzymes in the upper intestinal tract to glucose monomers (even using high daily doses, e.g., 10–20 g/kg). Following p.o. administration γ-CD remained intact, i.e., almost no absorption (0.1 %) was observed and it was practically not metabolized after parenteral administration (LD50 oral, rat ≫8,000 mg/kg; LD50 IV, rat ≈4,000 mg/kg) (Del Valle 2003).
Comparing the toxicological profile of the three natural CDs, γ-CD seems to be the least toxic. But its complexes normally have limited solubility in aqueous solutions and tend to self-aggregate; therefore, its complexing abilities are limited compared to those of β-CD and some water-soluble β-CD derivatives (Table 5).
4.2 Metabolism and Pharmacokinetics
4.2.1 Cyclodextrins
Regarding physicochemical and biological characteristics, CDs (ring dextrins) are very similar to water-soluble linear dextrins, but owing to their cyclic structure, they are more resistant to hydrolysis (enzymatic and nonenzymatic) than linear ones (Kurkov and Loftsson 2012). Contrary to starch, CDs are generally resistant to β-amylases, so they are not hydrolyzed from the nonreducing ends, but they cannot resist to the slow hydrolysis caused by α-amylases (hydrolysis from within the carbohydrate chain). α-CD and β-CD are not affected by the stomach acids and salivary and pancreatic enzymes during digestion, but γ-CD is digested partly by these amylases in the GI tract. The mechanism involved in the CDs’ hydrolysis resistance is due to all bridge oxygens being hidden within the central cavity; this hydrolytic rate will depend on several factors, namely, the ring size and fraction of free CD (Kurkov and Loftsson 2012).
Linear dextrins as well as starch are digested mainly into glucose through a stepwise enzymatic hydrolysis process which starts when in contact with salivary α-amylase, but by p.o. administration this is overcome as in the stomach the enzyme is inactivated (Dona et al. 2010). Some nonenzymatic specific acid hydrolysis of the dextrins can occur in the stomach, but this phenomena can be delayed by the formation of complexes with food lipids (Singh et al. 2010). In the small intestine (neutral pH), where pancreatic fluid containing α-amylase is released, enzymatic hydrolysis occurs. The dextrin substrates that remained intact along the above enzymatic process are finally submitted to bacterial digestion when they reach the lower sections of the intestine.
Thus, the most important pharmacokinetic parameters for these macromolecules are urinary clearance and hepatic uptake (Nishikawa et al. 1996). As it was shown by several authors, both natural CDs and their derivatives are susceptible to bacterial digestion in the GI tract (Antlsperger and Schmid 1996; Irie and Uekama 1997; Zhou et al. 1998; Zuo et al. 2002; Van Ommen et al. 2004; Stella and He 2008).
Natural CD pharmacokinetics are very similar to each other and to the linear dextrins with similar molecular weights (MW). The insignificant amount that is absorbed from the GI tract after p.o. administration is made by passive diffusion and can be explained by the bulky and hydrophilic nature of the CDs. After absorption, CDs are eliminated by the renal route without undergoing significant metabolism. Any remaining CD is eliminated by other pathways (liver metabolism and biliary excretion) similarly to low MW dextrans.
The main elimination process is dependent on the administration route: Following p.o. administration in rats and dogs, HP-β-CD was mainly excreted via the feces, whereas after IV administration, this CD was excreted via the kidneys. In the case of humans, this excretion process mainly occurs via the kidneys (Gould and Scott 2005). The t1/2 of the elimination phase (natural CDs) ranged approx. between 1.4 and 2 h, and the volume of distribution (VD) was approx. 0.2 L kg−1. The pharmacokinetic studies showed that over 90 % of parenterally administered CD will be eliminated from the body within approximately 6 h and over 99.9 % within 24 h (Kurkov and Loftsson 2012). The absorption of natural CDs and their derivatives following oral administration in the rat is summarized in Table 6.
After being absorbed CDs are distributed to several organ tissues, such as the kidney, urinary bladder, liver, adrenal gland, and others (Gerloczy et al. 1990; Monbaliu et al. 1990; Antlsperger and Schmid 1996; Kubota et al. 1996; De Bie et al. 1998; Van Ommen et al. 2004). The absorption of β-CD-methylated derivatives in rats were 6.3–9.6 % for DM-β-CD and 0.5–11.5 % for M-β-CD (Mosher and Thompson 2002). The HP-β-CD oral bioavailability (itraconazoleoral solution) in humans was estimated to be less than 1 % (De Repentigny et al. 1998; Stevens 1999). The IV administration of β-CD and HP-β-CD to permanently cannulated rats resulted in a pharmacokinetic behavior of both CDs similar to that of inulin, showing a rapid distribution over extracellular fluids and elimination through glomerular filtration (Frijlink et al. 1990). CDs via IV route disappeared rapidly from systemic circulation, as they are rapidly eliminated by the kidney, almost in intact form. This makes the kidney the organ with the highest level of CDs among all tissues. Thus, renal insufficiency could result in CD accumulation. As an example, it was observed that after IV bolus administration (10 mg kg−1) of M-β-CD, its concentration in the kidneys (mainly in the renal cortex) remained almost at the same level for at least 6 days (Antlsperger and Schmid 1996; Slain et al. 2001; Gould and Scott 2005; Von Mach et al. 2006; Stella and He 2008).
The β-CD steady-state volume of distribution (Vdss) and most of its derivatives in all animal species tested correspond well with the respective extracellular fluid volume (Table 7). Thus, it can be concluded that, after IV administration, CDs distribute mainly in the extracellular compartments without involving the deep compartments or storage pools (Kleijn et al. 2011). Methylated β-CD has a larger V dss and longer t ½ compared to other CD derivatives which may be due to its ability to interact with cellular membranes and its hemolytic activity (Thompson 1997). The total plasma clearance for HP-β-CD and SBE-β-CD in all species tested is similar to the glomerular filtration rate of individual species (Davies and Morris 1993). In these cases 100 % of an IV dose was recovered in the urine within 6–12 h (Davies and Morris 1993). Most CDs disappear from tissues dramatically within the first several hours after administration. For example, the level of SBE-β-CD in most tissues decreased by more than 90 %; even in the kidney, SBE-β-CD was reduced by at least 60 % from 0.1 to 1 h following IV bolus injection of 600 mg/kg SBE-β-CD in the rat (Stella and He 2008).
4.2.2 Complexes
The partitioning of the drug in its different forms (dissolved free drug molecules, dissolved complex, solid free drug, and solid complex) depends on the solubility of the free drug and the complexed drug in the given medium, the stability constant of the CD-drug complex, the molar ratio of the components, and the volume of the liquid phase. The same complex may provoke different – enhanced or decreased – biological responses depending on the additional amount of CD or even on the volume of water consumed.
It has generally been believed that following oral administration only an insignificant amount of CD is absorbed simultaneously with the drug, i.e., only free drug molecules can enter the circulation and the increasing excess of the remaining CD will push the equilibrium towards complex formation. CD acts primarily as a carrier agent to the site of absorption transporting the more or less hydrophobic guest molecule through an aqueous milieu to the lipophilic membrane of cells in the GI tract. There the guest molecule is absorbed, since the membrane has a higher affinity for a lipophilic guest molecule than the CD itself. If the complex is very stable or the CD concentration is high, the equilibrium is greatly shifted towards complexation and absorption is considerably hindered. Some studies have indicated slow absorption of some CDs by passive diffusion across intestinal membranes, which seem to be promoted in the presence of bile salts and Ca2+-chelating agents indicating absorption by the paracellular pathway. It is unclear whether GI tract absorption of drug-CD complexes may constitute a significant level of absorption under certain conditions, but in the case of pulmonary delivery where the barrier membranes are much thinner, this possibility should be considered.
In a model for in vivo drug release, the first step must be the dissolution of the solid adducts (Fig. 5). There then exists an equilibrium between the dissolved complex and the released drug. Only the dissolved, non-complexed drug can be absorbed (Cabral-Marques 1994c).
4.3 Biotechnological/Bioengineering Approaches
CD has been used in several biotechnological/bioengineering studies, some of which are described below:
It is not easy to predict drug absorption after its complexation with CD due to the large range of interacting parameters and their influence on free drug concentration.
Molecular modeling can help by making predictions and providing orientations for the development of new complexes that can be formulated in pharmaceutical dosage forms. Neutral compound complex model demonstrates the mechanism behind a possible variation (increase, decrease or no effect) in the absorption when CD is dosed as an inclusion complex. A model for predicting the CD effect on drug bioavailability, when administered as inclusion complex, was used. This model involved mass transport expressions for drug dissolution and absorption and pseudo-equilibrium D•CD complexation. Its predictions were compared with in vitro and in vivo experimental results allowing to predict when CD can be delivered as a preformed complex with drug to enhance bioavailability (Gamsiz et al. 2013).
Different polymers such as plasticized poly (vinyl chloride) (PVC-P), poly (ethylene oxide) (PEO), PEO/poly (propylene oxide) (PPO), and copolymers, e.g., Pluronic F68 (F68), were studied in order to obtain a novel modified biomaterial surface using CDs for increased blood compatibility. The β-CD-PEO and β-CD-F68 associations in certain feeding ratio were synergistic in producing the desired effect (Zhao and Courtney 2006).
Hydrogels have suitable properties for wound-dressing use due to its good biocompatibility and maintenance of a moist environment for better healing. The efficacy of these platforms can be improved by the use of CDs as cross-linking agents. The association hydrogels-CDs may allow the moist environment required for the healing process and the moiety with the ability to protect and modulate the release of bioactive molecules (Pinho et al. 2013). Furthermore, the development of the platforms using CD-containing polyrotaxanes is expected to provide a new paradigm for biomaterials. Thus, the CD-based biodegradable polypseudorotaxane hydrogels could be used as a promising injectable drug delivery system for sustained and controlled drug release. The polyrotaxanes with drug- or ligand-conjugated CDs threaded on a polymer chain with a biodegradable end group could be useful for controlled and multivalent targeted delivery. In the field of gene delivery, cationic polyrotaxanes consisting of multiple OEI-grafted CDs threaded on a block copolymer chain are attractive non-viral gene carries due to the strong DNA-binding ability, low cytotoxicity, and high gene delivery capability (Li et al. 2011).
The bioactive compounds from plants (polyphenolics, alkaloids, and polysaccharides) have well-documented pharmacological properties and have been widely used by the food, cosmetic, and pharmaceutical industries due to its advantages, such as high levels of biocompatibility, low toxicity and good availability. Polyphenolics are currently the major group of interest in view of their anti-inflammatory, antimicrobial, and antioxidant properties, as well as their availability in the human diet (Cowan 1999; Aridogan et al. 2002; Belščak-Cvitanović et al. 2011; Gou et al. 2011). Many studies have been published regarding the encapsulation of natural polyphenolic agents by CDs, for food and drug delivery proposes. CDs have a capacity of improving their aqueous solubility, protect them from elevated temperatures, pH, and light- or moisture-induced degradations increasing their bioavailability. In the case of flavonoids, the CD derivatives are the best choices to achieve an efficient complexation (Pinho et al. 2014).
Monochlorotriazinyl-β-cyclodextrin (β-CDMCT) has been used as a great tool for surface modification of natural and synthetic fibers (polyester, polyamides, and polyacrylics). These materials after being grafted onto celluloses substrates can be used for fragrance release, odor adsorption (sheets and personal clothing), controlled release (antibacterial, fungicide, or insect repellents), UV protection, and stabilization of active ingredients due to CD cavities. These platforms in β-CD cavities can include an insect repellent and an insecticide. In addition this new tool was designed for the treatment of materials (such as bed nets, curtains, specific clothing, military uniforms, etc.) in order to prevent man-vector contact (Reuscher and Hinsenkorn 1996; Romi et al. 2005).
The structural CD properties make them suitable building blocks to be used in polymeric reactions, since they can be grafted to polymers (natural/synthetic) resulting in different polymer architectures (Zhang and Ma 2013).
Molecular complexation with CDs already cited play an important role in biotechnology and bioengineering area in the domain of selectivity, separation, and solubilization of various biomolecules.
4.4 Applications of CDs
Since CDs are versatile molecules that offer unique features and have negligible cytotoxic effects, they have been widely used in many industrial products, technologies, and analytical methods (Cabral-Marques 1994c; Singh et al. 2002; Del Valle 2003; Cabral-Marques 2008). Some examples of applications are the following.
4.4.1 Pharmaceuticals
CDs have been widely used in pharmaceutical industries, being in the most of the cases as auxiliary substances, improving stability, bioavailability, and organoleptic properties (e.g., palatability, masking odors) of active compounds in multiple pharmaceutical dosage forms (Del Valle 2003; Carrier et al. 2007; Miller et al. 2007; Cabral-Marques 2010). These versatile sugar molecules enabled the production and reintroduction of numerous active substances that, owing to stability, compatibility, or absorption problems, were not in use (Cabral-Marques 1994c). Shortly, the CDs’ multifunctional features have been exploited in drug delivery system being potential candidates in many applications because of their ability to alter the physical, chemical, and biological properties of guest molecules through the formation of inclusion complexes (Uekama et al. 1998; Cabral-Marques 2008). All these improvements enabled their application in commercialized pharmaceutical products used in almost every drug delivery systems: α-CD (oral, parenteral), β-CD (dermal, oral, rectal, sublingual), HP-β-CD (ocular, oral, parenteral, rectal), DM-β-CD (dermal, nasal, ocular), SBE-β-CD (parenteral), and HP-γ-CD (ocular) (Cabral-Marques 2008; Tiwari et al. 2010). Among all CDs, β-CD is the most reasonably priced, thus the most used on industrial applications.
Oral delivery: The drug release in this route of administration is controlled either by dissolution, diffusion, osmotic systems, density, or pH (Tiwari et al. 2010).
CDs are particularly useful as they can be used as a way to reduce local drug irritation and increase drug absorption rate (Loftsson et al. 2005b). The hydrophilic CDs provide an enhancement of stability, solubility, dissolution rate, and wettability of poorly water-soluble drugs by means of complex formation (Carrier et al. 2007). CDs are supposed to act only as carriers and help to transport the drug through an aqueous medium to the lipophilic absorption surface in the GI tract. Buccal and sublingual routes have also been an effective way to deliver rapid-dissolving drug-CD complexes. In this case, a rapid increase in the systemic drug concentration takes place along with the avoidance of systemic and hepatic first-pass metabolism (Tiwari et al. 2010).
Pulmonary delivery: Pulmonary administration has been gaining an increased importance for therapeutic usage due to lung’s anatomical and physiological characteristics like large surface area available (~100 m2), high irrigation (5 L/min), very thin absorption membrane (0.1–0.2 μm), and relatively low enzymatic activity (Pilcer and Amighi 2010). This is normally an attractive route for treatment of local diseases (e.g., asthma, DPOC) but is also interesting for systemic delivery. However, this route is usually limited by the characteristics of drugs used, low aqueous solubility, and slow drug dissolution (Loftsson et al. 2005b). CDs are used to solve these drawbacks and to improve the pulmonary delivery of drugs either systemically or locally. Formulations of insulin delivered via pulmonary route (powders and liquids) have low bioavailability (10–15 %), and thus, to get the right dose, a high drug loading is needed in drug delivery system (Ramalhete et al. 2001). Formulations with penetration enhancers (with proven efficacy via other administration routes) such as CDs could help this matter (Cabral-Marques et al. 1991). Current DPIs (Dry Powder Inhalers) for treatment of respiratory diseases generally deliver only 10–20 % of the nominal dose to the site of action. It is possible to engineer particles by spray-drying and using CDs to improve this drawback allowing a more efficient drug delivery to the site of action, with fewer systemic effects than oral therapy (Vozone and Cabral-Marques 2002; Almeida and Cabral-Marques 2004; Drumond et al. 2014).
Nasal delivery: This is another effective route that avoids the extensive GI breakdown and hepatic first-pass metabolism. Due to nasal mucosa’s good permeability, this delivery route is a novel approach for systemic delivery of high potency drugs with a low oral bioavailability. As lipophilic CDs can interact with biological barriers (without affecting their barrier function), they have the ability to enhance the drug delivery – a property which makes CDs ideal penetration enhancers for intranasal administration. Methylated CDs are the most commonly used and widely studied. They have shown in several studies very promising results being efficient absorption enhancers, namely, in the delivery of peptides and hormones (Merkus et al. 1999; Loftsson et al. 2005b; Tiwari et al. 2010).
Ocular delivery: In this type of delivery systems, the most used dosage form is the eye drop due to easy instillation in the eye. However, eye drops are a great formulation challenge due to the high probability of its inability to sustain high local concentration of drug (Tiwari et al. 2010). By this reason CDs have been used to overcome these problems as they present possible advantages in ophthalmic use, such as increase in solubility and/or stability and reduction or avoidance of side effect of drugs (e.g., discomfort and irritation) (Torres Marques et al. 1996; Loftsson et al. 2012). One of the prerequisites for a new vehicle to be used in ophthalmic preparations is that it is not irritating to the ocular surface, because irritation causes reflex tearing and blinking, which result in a fast washout of the instilled drug (SáCouto et al. 2014). Hydrophilic CDs do not penetrate eye cornea biological barriers but enhance the ocular bioavailability of lipophilic drugs by keeping them in solution (Cabral-Marques 2008).
Rectal delivery: This route is by far the chosen one to deliver drugs to the unconscious patients, children and infants. Despite offering a relatively low area for drug absorption, which leads to an erratic release of drugs, the rectal mucosa represents a potential site for delivery of drugs with limitations by the oral route (e.g., organoleptic problems, pH degradation, high first-pass metabolism) (Tiwari et al. 2010). Beraldo et al. (2002) has shown that CDs are quite useful to solve the erratic release problems of this route.
Dermal delivery: This is the most sophisticated and more reliable form to administrate the drug through skin, either for local or systemic action (Tiwari et al. 2010). CDs have a significant safety margin in dermal application and can be used to optimize the transdermal delivery of drugs. CDs improve drugs’ solubility and/or stability in topical preparations, consequently enhancing the transdermal absorption of drugs, to sustain the drug release from the vehicle and to avoid undesirable side effects associated with dermally applied drugs (Waleczek et al. 2003; Santos et al. 2004; Loftsson et al. 2005b). CDs may interact with some components of the skin and the lipids such as cholesterol and triglycerides and consequently induce a temporary change in the skin barrier function and an enhancement in the drug absorption. It was shown that DM-β-CD has higher skin permeation effect than HP-β-CD (Cabral-Marques 2008).
4.4.2 Bioconversion and Fermentation
The efficiency of bioconversion and fermentation processes is often restricted by the inhibitory or toxic influence from either the substrate or the conversion products on the biocatalyst. Another problem often found on most organic substrates is their solubility in water which complicates the amount of substrate accessible to the biocatalyst. In order to overcome process limitations such as low solubility of lipophilic substrates, CDs can be added to the bioconversion or fermentation media. In addition CDs may provide a reduction of toxicity by complexation with toxins and biocompatibility improvement (Bar 1989; Cabral-Marques 2010).
4.4.3 Environment Protection
CDs are important to environmental science in terms of remediation by complexation of organic contaminants/pollutants and heavy metals from soil, water, and atmosphere. After treating wastewaters containing environmentally unacceptable aromatic compounds (phenol, p-chlorophenol and benzene) with β-CD, the initial levels of these aromatic hydrocarbons were significantly reduced. The same CD benefic actions may also be used in the treatment of gaseous effluent from chemical industries (Cabral-Marques 1994b; Del Valle 2003).
4.4.4 Agrochemical Industry
CDs may be used to improve a variety of properties of bactericides, insecticides, herbicides, and fungicides. Complex formation with β-CD has been reported, including examples of increased or decreased activity of pesticides (Cabral-Marques 1994b).
4.4.5 Catalysis
The CDs ability to mimetize enzymes, i.e., molecular recognition phenomenon, led them to be used in catalysis. Thus, CDs have to be modified through substituting various functional compounds or by attaching reactive groups. In addition CDs possess the ability of enantiomeric recognition. Resulting from the chelating effect of the CD catalysts, rates of reaction may be enhanced by almost 1,000-fold when compared to free solution (Del Valle 2003).
4.4.6 Analytical
The CDs are very useful in separation process due to its molecular recognition ability to discriminate positional isomers, functional groups, and homologues/enantiomeric compounds. Depending on the substrate to be separated, the choice of the CDs is essential since shape, size, and selectivity will influence separations. CDs have been used in HPLC and GC (being CDs in the stationary phase columns), in NMR (chiral shift agents), in circular dichroism (selective agents altering spectra), and also in electrochemical chemistry (to mask contaminating compounds) (Del Valle 2003). These substances serve as an ideal selector by molecular recognition and further enhance the complex forming ability and selectivity in various type of separations (Eastburn and Tao 1994; Han 1997; Loung and Nguyen 1997; Szejtli 1998; Del Valle 2003; Cabral-Marques 2010).
4.4.7 Food and Flavors
In food industry the CDs are used as multifunctional food ingredients. They can be used as carriers for molecular encapsulation forming inclusion complexes with a variety of molecules including fats, aromatic agents, flavors, and colors. The inclusion complexes improve both physical and chemical stability of sensitive ingredients leading to better conservation and, consequently, to extended food shelf life. CDs also can act as a controlled release agent of desired food constituents and can provide a promising alternative to the conventional encapsulation technologies by removing and/or masking undesirable components (e.g., removal of cholesterol from butter, eggs, milk; decreasing of juice’s bitterness). In addition, CDs can protect the food ingredient throughout many rigorous food-processing methods of freezing, thawing, and microwaving (Prasad et al. 1999; Del Valle 2003; Cabral-Marques 2010).
4.4.8 Cosmetics, Toiletry, and Personal Care
Cosmetic preparations are another area where CDs have been largely used to protect molecules against physical and chemical instabilities (e.g., oxidation, decomposition, hydrolysis). By complex formation included guest molecules may increase their stability, suppress volatility (in the case of perfumes), reduce/prevent skin irritation, and improve room fresheners and detergent’s action. Active ingredients are released from inclusion compounds by controlled release. In summary, it is possible to say that major benefits of CDs in the cosmetics, toiletry, and personal care products are stabilization, odor control, process improvement upon conversion of liquids to solids, absorption increase/decrease of various compounds into skin, flavor protection, enhanced water solubility, and thermal stability of oils. Moreover, CDs are used in toothpaste, lipsticks, skin creams, liquid and solid fabric softeners, paper towels, tissues, shampoos, and deodorants (Del Valle 2003; Cabral-Marques 2010).
4.4.9 Packaging and Textile Industry
Textile industry is another area in which CDs are increasingly attracting attention (Cabral-Marques 2010). Fabrics can be imbued with novel properties by means of these substances. In order to permanently transfer the versatile properties of CDs to textiles, Wacker-Chemie (the world’s largest producer of γ-CDs) covalently attached reactive CD derivative with monochlorotriazinyl (MCT) substituents to the fiber. This substituted CD provided excellent textile finishing to cottons, blended materials, and woolens. Using hydrophobic tosyl derivative of β-CDs, threefold increase in the binding of fluorescent dye to the polyester fiber was attained.
CDs also play a major role in the packaging industry. Inclusion complex containing oily antimicrobial and volatile agents are coated on a water-absorbing sheet with a natural resin binder, which is used for wrapping fresh products. It was found that food-packaging bag manufactured using CD with ethylene-tetracyclo-3-dodecane copolymer and hinokitiol showed no odor and good antifungal properties after 1 week of storage at room temperature, which proved useful for food-packaging materials (Hedges 1998; Ishibashi et al. 1999; Hirose and Yamamoto 2001).
5 Current Regulatory State
Despite of being characterized as pharmacologically inactive compounds, pharmaceutical excipients are treated as active compounds in the regulatory perspective, especially when used for the first time in humans (Demerlis et al. 2009; Koo 2011; Osterberg et al. 2011). Their acceptance is often supported by previous usage in commercialized pharmaceutical products or in the food industry. This is also valid if the excipient is already being used at the same levels and administration routes as in marketed products. In these cases a full safety evaluation may not be needed (Kurkov and Loftsson 2012).
The regulatory status of CDs has evolved over the last years even with the skepticism within the regulatory agencies concerning their usage. Consensus seems to be building among regulators that CDs are excipients and not part of the drug substance although divergent opinions exist (Brewster and Loftsson 2007). Products containing CDs undergo rigorous evaluation, and their strengths and weaknesses are understood and agencies will become more comfortable with them and lower the barriers to their use (Davis and Brewster 2004; Loftsson et al. 2004; Stella and He 2008). Table 8 shows an overview of the food approval status of CDs by the different worldwide regulatory agencies.
Monograph for natural β-CD is listed in some pharmacopoeia sources such as the US Pharmacopoeia/National Formulary (USP/NF), European Pharmacopoeia (Ph. Eur.), and Japanese Pharmaceutical Codex (JPC). α-CD is also listed in the Ph. Eur., USP/NF, and JPC; γ-CD is referenced in the JPC and soon will be included in the Ph. Eur. and USP/NF. A monograph for HP-β-CD is available in the Ph. Eur., and a draft has been circulated for the USP/NF; SBE-β-CD can be found in the USP/NF. Other derivatives are not yet compendial but efforts are being made for their inclusion. α-CD, β-CD, and γ-CD were also introduced into the generally regarded as safe (GRAS) list of the FDA for use as a food additive in 2004, 2001, and 2000, respectively; HP-β-CD and γ-CD are cited in the FDA’s list of Inactive Pharmaceutical Ingredients. SBE-β-CD is also available in various dosage forms and listed in the FDA’s compilation of Inactive Pharmaceutical Ingredients (Cabral-Marques 2010; Kurkov and Loftsson 2012).
Currently different marketed pharmaceutical products (Table 9) as well as numerous food products (Cabral-Marques 2010) can be found using different CDs: α-CD, β-CD, HP-β-CD, RM-β-CD, SBE-β-CD, γ-CD, and HP-γ-CD.
6 Conclusion/Prospects
Since the begin of nineteenth century CDs have been showing their potentialities, and up to today they have gained a great importance and different applications in distinct areas from pharmaceutical and food to chemical and environmental industries. So a prosperous future can be envisaged to CDs being one of the most adaptable and relevant excipient. All this was only possible due to their remarkable characteristics which make them a versatile compound with the ability to form inclusion complexes with guest molecules possessing a hydrophobic moiety (Tiwari et al. 2010).
Due to science evolution, the discovery of new molecules with solubility, bioavailability, and permeability limitations or other undesirable properties (stability, taste and odor, irritation potential, etc.) raises the need for CDs’ usage as they can be useful tools for scientists.
CDs can be useful drug carriers in delivery systems as they are bio-adaptable particularly in parenteral applications (especially HP-β-, SBE-β-, and maltosyl-β-CDs), having the ability to control the rate and time of drug release. Peracylated CDs may serve as novel hydrophobic carriers to control the release of water-soluble drugs including peptides and proteins in various routes of administration. Amphiphilic or ionizable CDs can modify the rate or time of drug release and bind to the surface membrane of cells, which may be used for the enhancement of drug absorption across biological barriers. A combination of molecular encapsulation with other pharmaceutical excipients is effective and valuable in the improvement of carrier properties of CDs. Conjugates of a drug with CDs can be a versatile drug site-specific carrier for colon therapy; they form a new class of colon-targeting prodrugs (Uekama et al. 1998; Uekama 2004; Li and Loh 2008).
There are more than 100 different CD derivatives commercially available as fine chemicals, mainly for use in chromatography, in diagnostics, and as intermediate for further synthesis. The ideal derivative does not exist yet. It is expected that more derivatives will be developed. For organ or receptor targeting, extremely stable, bio-adaptable, and specific affinity-showing CD complexes will be needed (Cabral-Marques 2008; Kurkov and Loftsson 2012).
Despite of all the unique architecture and the chelating properties that CDs present, the usage of this excipient is not by itself a reason to achieve a successful goal without previous studies. In fact a great knowledge of the characteristics of all the compounds intended to be used (CDs, guest molecule, additives to the product) and prior work are extremely necessary to try to predict and find out any possible interaction between them, just because these interactions can adversely affect the performance of these constituents, which can lead to incompatibilities, formulation problems, lack of stability, etc., and consequently have a great impact in the final commercialized product. In conclusion, the ideal scenario would be to choose the CD that has the most appropriate characteristics to include the desired guest molecule, predict all the different variables that can influence the complex formation process, and in the end be able to prepare a product with the desirable properties that can be an innovation or an improvement and at last but not the least be economically viable.
References
Almeida R, Cabral-Marques HM (2004) Pulmonary administration of beclomethasone: gamma-cyclodextrin complex. In: Duchêne D (ed) Proceedings of the 12th international cyclodextrin symposium, Montpellier. Editions de Santé/APGI Publishing, Paris, pp 889–892
Al-Sharawi SZR, Ibrahim ASS, El-Shatoury EH, Gebreel HM, Eldiwany A (2013) A new low molecular mass alkaline cyclodextrin glucanotransferase from Amphibacillus sp. NRC-WN isolated from an Egyptian soda lake. Electron J Biotechnol 16:1–13
Alves-Prado HF, Carneiro AAJ, Pavezzi FC, Gomes E, Boscolo M, Franco CML, da Silva R (2008) Production of cyclodextrins by CGTase from Bacillus clausii using different starches as substrates. Appl Biochem Biotechnol 146:3–13
Antlsperger G, Schmid G (1996) Toxicological comparison of cyclodextrins. In: Szejtli J, Szente L (eds) Proceedings of the 8th international symposium on cyclodextrins, Budapest. Kluwer, Dordrecht, pp 149–155
Aridogan BC, Baydar H, Kaya S, Demirci M, Ozbasar D, Mumcu E (2002) Antimicrobial activity and chemical composition of some essential oils. Arch Pharm Res 2:860–864
Arima H, Tsutsumi T, Yoshimatsu A, Ikeda H, Motoyama K, Higashi T, Hirayama F, Uekama K (2011) Inhibitory effect of siRNA complexes with polyamidoamine dendrimer/α-cyclodextrin conjugate (generation 3, g3) on endogenous gene expression. Eur J Pharm Sci 44:375–384
Babu RJ, Pandit JK (2004) Effect of cyclodextrins on the complexation and transdermal delivery of bupranolol through rat skin. Int J Pharm 271:155–165
Bar R (1989) Cyclodextrin-aided bioconversions and fermentations. Trends Biotechnol 7:2–4
Bas GL, Rysanek N (1987) Structural aspects of cyclodextrins. In: Duchêne D (ed) Cyclodextrins and their industrial uses. Editions de Santé, Paris, pp 107–130
Bellringer ME, Smith TG, Read R, Gopinath C, Oliver P (1995) β-Cyclodextrin: 52-week toxicity studies in the rat and dog. Food Chem Toxicol 33:367–376
Belščak-Cvitanović A, Stojanovićb R, Manojlović V, Komes D, Cindrić IJ, Nedović V, Bugarski B (2011) Encapsulation of polyphenolic antioxidants from medicinal plant extracts in alginate–chitosan system enhanced with ascorbic acid by electrostatic extrusion. Food Res Int 44:1094–1101
Bender ML, Komiyama M (1978) Cyclodextrin chemistry. In: Springer-Verlag, Berlin
Beraldo H, Sinisterra RD, Teixeira LR, Vieira RP, Doretto MC (2002) An effective anticonvulsant prepared following a host-guest strategy that uses hydroxypropyl-beta-cyclodextrin and benzaldehyde semicarbazone. Biochem Biophys Res Commun 296:241–246
Brewster ME, Loftsson T (2007) Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev 59:645–662
Cabral-Marques HM (1994a) Structure and properties of cyclodextrins. Inclusion complex formation. Rev Port Farm 44:77–84
Cabral-Marques HM (1994b) Applications of cyclodextrins. Thermodynamic aspects of cyclodextrin complexes. Rev Port Farm 44:85–96
Cabral-Marques HM (1994c) Cyclodextrins’ derivatives. Absorption, toxicity, metabolism and fate. Rev Port Farm 44:147–156
Cabral-Marques HM (2008) Propriedades e Utilização das Ciclodextrinas como Transportadores de Fármacos/properties and uses of cyclodextrins as drug carriers. Rev Lusóf Ciên Tecnol Saúde 5:69–81
Cabral-Marques HM (2010) A review on cyclodextrin encapsulation of essential oils and volatiles. Flavour Fragr J 25:313–326
Cabral-Marques HM, Hadgraft J, Kellaway IW, Taylor G (1991) Studies of cyclodextrin inclusion complexes. Part IV. The pulmonary absorption of salbutamol from a complex with HP-beta-cyclodextrin in rabbits. Int J Pharm 77:303–307
Carrier RL, Miller LA, Ahmed I (2007) The utility of cyclodextrins for enhancing oral bioavailability. J Control Release 123:78–99
Charoenchaitrakool M, Dehghani F, Foster NR (2002) Utilization of supercritical carbon dioxide for complex formation of ibuprofen and methyl-beta-cyclodextrin. Int J Pharm 239:103–112
Cheirsilp B, Suleeporn K, Maneerat S (2010) Kinetic characteristics of β-cyclodextrin production by cyclodextrin glycosyltransferase from newly isolated Bacillus sp. C26. Electron J Biotechnol 13:1–8
Chin TF, Chung PH, Lach JL (1968) J Pharm Sci 57:44
Ciobanu A, Landy D, Fourmentin S (2013) Complexation efficiency of cyclodextrins for volatile flavor compounds. Food Res Int 53:110–114
Cowan MM (1999) Plant products as antimicrobial agents. Clin Microbiol Rev 12:564–582
Cramer F (1982) Cyclodextrin – a paradigmatic model. In: Szejtli J (ed) Proceedings of I international symposium on cyclodextrins, Budapest. Reidel/Akadémiai Kiadó, Dordrecht/Budapest, pp 367–376
Cramer F (1987) Cyclodextrins and their industrial uses. In: Duchêne D (ed) Introduction. Editions de Santé, Paris, pp 11–18
Cramer F, Hettler H (1967) Naturwissenschaften 54:625
Cramer F (1954) Einschlussverbindungen. Springer, Berlin
Croft AP, Bartsch RA (1983) Synthesis of chemically modified cyclodextrins. Tetrahedron 39:1417–1474
Daletos G, Papaioannou G, Miguel G, Cabral-Marques HM (2008) Improvement of organoleptic properties of thymol and carvacrol using β-cyclodextrin. In: Ueda H (ed) Proceedings of the 14th international cyclodextrin symposium, Kyoto. The Society of Cyclodextrins, Tokyo, pp 291–295
Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095
Davis ME, Brewster ME (2004) Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov 3:1023–1035
De Bie AT, Van Ommen B, Bar A (1998) Disposition of β-cyclodextrin in germ-free and conventional rats. Regul Toxicol Pharmacol 27:150–158
De Repentigny L, Ratelle J, Leclerc JM, Cornu G, Sokal EM, Jacqmin P, De Beule K (1998) Repeated dose pharmacokinetics of an oral solution of itraconazole in infants and children. Antimicrob Agents Chemother 42:404–408
Del Valle EMM (2003) Cyclodextrins and their uses: a review. Process Biochem 39:1033–1046
Demerlis C, Goldring J, Velagaleti R, Brock W, Osterberg R (2009) Regulatory update: the IPEC novel excipient safety evaluation procedure. Pharm Technol 33:72–82
Dona A, Pages G, Gilbert R, Kuchel P (2010) Digestion of starch: in vivo and in vitro kinetic models used to characterise oligosaccharide or glucose release. Carbohydr Polym 80:599–617
Drumond N, Sá Couto A, Costa A, Cabral-Marques HM (2014) Study of aerodynamic and release properties of inhaled particles containing cyclodextrins. J Incl Phenom Macro Chem. doi:10.1007/s10847-014-0400-z
Duchêne D, Wouessidjewe D (1990a) Pharmaceutical uses of cyclodextrins and derivatives. Drug Dev Ind Chem 16:2487–2499
Duchêne D, Wouessidjewe D (1990b) Physicochemical characteristics and pharmaceutical uses of cyclodextrin derivatives, Part I. Acta Pharm Technol 14:26–34
Duchêne D, Vaution C, Glomot F (1986) Cyclodextrins, their value in pharmaceutical technology. Drug Dev Ind Chem 12:2193–2215
Eastburn SD, Tao BY (1994) Applications of modified cyclodextrins. Biotechnol Adv 12:325–339
Endo T, Ueda H, Kobayashi S, Nagai T (1995) Isolation, purification and characterization of cyclomalto-dodecaose (η-CD). Carbohydr Res 269:369–373
Endo T, Nagase H, Ueda H, Kobayashi S, Nagai T (1997a) Isolation, purification, and characterization of cyclomaltodecaose (ε-cyclodextrin), cyclomaltoundecaose (ζ-cyclodextrin) and cyclomaltotridecaose (θ-cyclodextrin). Chem Pharm Bull 45:532–536
Endo T, Nagase H, Ueda H, Shigihara A, Kobayashi S, Nagai T (1997b) Isolation, purification, and characterization of cyclomaltotetradecaose (ι-cyclodextirn), cyclomaltopentadecaose (κ-cyclodextrin), cyclomaltohexadecaose (λ-cyclodextrin), and cyclomaltoheptadecaose (μ-cyclodextrin). Chem Pharm Bull 45:1856–1859
Endo T, Nagase H, Ueda H, Shigihara A, Kobayashi S, Nagai T (1998) Isolation, purification and characterization of cyclomaltooctadecaose (ν-cyclodextrin), cyclomaltononadecaose (ξ-cyclodextrin), cyclomaltoeicosaose (ο-cyclodextrin) and cyclomaltoheneicosaose (π-cyclodextrin). Chem Pharm Bull 46:1840–1843
Fages J, Rodier E, Chamaou A, Baron M (2007) Comparative study of two processes to improve the bioavailability of an active pharmaceutical ingredient: kneading and supercritical technology. Ec. des Mines d’Albi, RAPSODEE Res. Cent. 217:19
Frank SG (1975) Inclusion compounds. J Pharm Sci 64:1585
French D (1957) The Schardinger dextrins. Adv Carbohydr Chem 12:189–260
French D, Pulley AO, Effenberger JA, Rougvie MA, Abdullah M (1965) Studies on the Schardinger dextrins. XII. The molecular size and structure of the delta-, epsilon-, zeta-, and eta-dextrins. Arch Biochem Biophys 111:153–160
Freudenberg K, Cramer F (1948) Die Konstitution der Schardinger Dextrine a, b und g. Z Naturforsch B 3:464
Freudenberg K, Meyer-Delius M (1938) Ber Dtsch Chem Ges 71:1596
Freudenberg K, Plankenhorn E, Knauber H (1947) Chem Ind 731
Frijlink HW, Visser J, Hefting NR, Oosting R, Meijer DK, Lerk CF (1990) The pharmacokinetics of β-cyclodextrin and hydroxypropyl-β-cyclodextrin in the rat. Pharm Res 7:1248–1252
Frömming KH (1987) In: Breimer DD, Speiser P (eds) Topics in pharmaceutical sciences. Elsevier, Amsterdam, p 169
Frömming KH, Szejtli J (1994) Cyclodextrins in pharmacy, Topics in inclusion science. Kluwer, Dordrecht
Frömming KH, Wedelich V, Mehnert W (1987) J Incl Phenom 5:625
Fujiwara T, Tanaka N, Kobayashi S (1990) Structure of δ-cyclodextrin•13.75 H2O. Chem Lett 739–742
Gamsiz ED, Thombre AG, Ahmed I, Carrier RL (2013) Model predicting impact of complexation with cyclodextrins on oral absorption. Biotechnol Bioeng 110:2536–2547
Gerloczy A, Antal S, Szathmari I, Muller-Horvath R, Szejtli J (1990) Absorption, distribution and excretion of 14C-labelled hydroxypropyl β-cyclodextrin in rats following oral administration. In: Duchéne D (ed) 5th international symposium on cyclodextrins, Paris. March de Sante, Paris, pp 507–513
Gil A, Chamayou A, Leverd E, Bougaret J, Baron M, Couarraze G (2004) Evolution of the interaction of a new chemical entity, eflucimibe, with γ-cyclodextrin during kneading process. Eur J Pharm Sci 23:123–129
Gou J, Zou Y, Ahn J (2011) Enhancement of antioxidant and antimicrobial activities of Dianthus superbus, Polygonum aviculare, Sophora flavescens, and Lygodium japonicum by pressure-assisted water extraction. Food Sci Biotechnol 20:283–287
Gould S, Scott R (2005) 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD): a toxicology review. Food Chem Toxicol 43:1451–1459
Grosse PY, Bressolle F, Rouanet P, Joulia JM, Pinguet F (1999) Methyl-β-cyclodextrin and doxorubicin pharmacokinetics and tissue concentrations following bolus injection of these drugs alone or together in the rabbit. Int J Pharm 180:215–223
Han SM (1997) Direct enantiomeric separations by high performance liquid chromatography using cyclodextrins. Biomed Chromatogr 11:259–271
Hedges RA (1998) Industrial applications of cyclodextrins. Chem Rev 98:2035–2044
Higashi T, Nishimura K, Yoshimatsu A, Ikeda H, Arima K, Motoyama K, Hirayama F, Uekama K, Arima H (2009) Preparation of four types of coenzyme Q10/gamma-cyclodextrin supramolecular complexes and comparison of their pharmaceutical properties. Chem Pharm Bull 57:965–970
Higuchi T, Connors KA (1965) Phase-solubility techniques. Adv Anal Chem Instrum 4:117–212
Hincal AA, Eroglu H, Bilensoy E (2011) Regulatory status of cyclodextrins in pharmaceutical products. In: Bilensoy E (ed) Cyclodextrins in pharmaceutics, cosmetic, and biomedicine: current and future industrial applications. Wiley, Hoboken
Hirose T, Yamamoto Y (2001) Hinokitol containing cyclo-olefin polymer compositions and their molding with excellent antimicrobial and gas barrier properties. Japanese Patent JP 55480
Ibrahim ASS, Al-Salamah AA, El-Tayeb MA, El-Badawi YB, Antranikian G (2012) A novel cyclodextrin glycosyltransferase from alkaliphilic Amphibacillus sp. NPST-10: purification and properties. Int J Mol Sci 13:10505–10522
Irie T, Uekama K (1997) Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. J Pharm Sci 86:147–162
Ishibashi M, Kashikura A, Ozaki S, Kawakubo H (1999) Water absorbing sheet for packaging fresh product. Japanese Patent JP 11285368
Jicsinszky L (2014) Cyclodextrin derivatives. CycloLab Cyclodextrin R&D Laboratory, Budapest. http://www.cyclolab.hu/elearning/synth_cd_jicsinszky.pdf. Accessed 10 June 2014
Jones SP, Grant DJW, Hadgraft J, Parr GD (1984) Cyclodextrins in pharmaceutical sciences. Part I. Preparation, structure and properties of cyclodextrins and cyclodextrin inclusion compounds. Acta Pharm Tech 30:213–223
Junco S, Casimiro T, Ribeiro N, Nunes P, Cabral-Marques HM (2002) A comparative study of naproxen-beta-cyclodextrin complexes prepared by conventional methods and using supercritical carbon dioxide. J Incl Phenom Macro Chem 44:117–121
Kitamura S (2000) Cyclic oligosaccharides and polysaccharides. In: Semlyen JA (ed) Cyclic polymers, 2nd edn. Kluwer, Dordrecht, p 125, Chapter 4
Kleijn HJ, Zollinger DP, Van Den Heuvel MW, Kerbusch T (2011) Population pharmacokinetic-pharmacodynamic analysis for sugamadex-mediated reversal of rocuronium-induced neuromuscular blockade. Br J Clin Pharmacol 72:415–433
Koizumi K, Sanbe H, Kubota Y, Terada Y, Takaha T (1999) Isolation and characterization of cyclic α-(1→4)-glucans having degrees of polymerization 9–31 and their quantitative analysis by high-performance anion-exchange chromatography with pulsed amperometric detection. J Chromatogr A 852:407–416
Koo O (2011) Application challenges and examples of new excipients in advanced drug delivery systems. Am Pharm Rev 14:60–68
Koutsou GA, Storey DM, Bär A (1999) Gastrointestinal tolerance of γ-cyclodextrin in humans. Food Addit Contam 16:313–317
Kriaa M, Dorra Ayadi DZ, Jemli S, Sahnoun M, Bejar S, Kammoun R (2012) Improvement of cyclodextrin glycosyltransferase (CGTase) production by recombinant Escherichia coli pAD26 immobilized on the cotton. Biologia 67:1049–1055
Kubota Y, Fukuda M, Muroguchi M, Koizumi K (1996) Absorption, distribution and excretion of β-cyclodextrin and glucosyl-β-cyclodextrin in rats. Biol Pharm Bull 19:1068–1072
Kurkov SV, Loftsson T (2012) Cyclodextrins. Int J Pharm 453:167–180
Larsen KL (2002) Large cyclodextrins. J Incl Phenom Macrocycl Chem 43:1–13
Lederer M, Leipzig-Pagani E (1996) A simple alternative determination for the formation constant for the inclusion complex between rutin and β-cyclodextrin. Anal Chim Acta 329:311–314
Li J, Loh X (2008) Cyclodextrin-based supramolecular architectures: syntheses, structures, and applications for drug and gene delivery. Adv Drug Del Rev 60:1000–1017
Li JJ, Zhao F, Li J (2011) Supramolecular polymers based on cyclodextrins for drug and gene delivery. Adv Biochem Eng Biotechnol 125:207–249
Lichtenthaler FW (2010) Carbohydrates: occurrence, structures and chemistry. In: Ullmann’s encyclopedia of industrial chemistry, 6th edn. Wiley-VCH, Weinheim
Lina BAR, Bär A (2004a) Subchronic oral toxicity studies with α-cyclodextrin in rats. Regul Toxicol Pharmacol 39:S14–S26
Lina BAR, Bär A (2004b) Subchronic (13-week) oral toxicity study of α- cyclodextrin in dogs. Regul Toxicol Pharmacol 39:S27–S33
Loftsson T, Brewster ME (2012) Cyclodextrins as functional excipients: methods to enhance complexation efficiency. J Pharm Sci 101:3019–3032
Loftsson T, Duchêne D (2007) Cyclodextrins and their pharmaceutical applications. Int J Pharm 329:1–11
Loftsson T, Brewster ME, Másson M (2004) Role of cyclodextrins in improving oral drug delivery. Am J Drug Deliv 2:261–275
Loftsson T, Hreinsdóttir D, Másson M (2005a) Evaluation of cyclodextrin solubilization of drugs. Int J Pharm 302:18–28
Loftsson T, Jarho P, Másson M, Järvinen T (2005b) Cyclodextrins in drug delivery. Expert Opin Drug Deliv 2:335–351
Loftsson T, Jansook P, Stefánsson E (2012) Topical drug delivery to the eye: dorzolamide. Acta Ophthalmol 90:603–608
Loung JH, Nguyen AL (1997) Achiral selectivity in cyclodextrin modified capillary electrophoresis. J Chromatogr A 792:431–444
Mabuchi N, Ngoa M (2001) Controlled release powdered flavour preparations and confectioneries containing preparations. Japanese Patent JP 128638
MacNicol DD, McKendrick JJ, Wilson DR (1978) Clathrates and molecular inclusion phenomenon. Chem Soc Rev 7:65–87
Matsuda H, Arima H (1999) Cyclodextrins in transdermal and rectal delivery. Adv Drug Deliv Rev 36:81–99
Menezes P, Serafini M, Santana B, Nunes R, Quintans L Jr, Silva G, Isac Medeiros I, Marchioro M, Fraga B, Santos M, Araújo A (2012) Solid-state β-cyclodextrin complexes containing geraniol. Thermochem Acta 548:45–50
Menezes P, Serafini M, Quintans-Júnior L, Silva G, Oliveira J, Carvalho F, Souza J, Matos J, Alves P, Matos I, Hădărugă D, Araújo A (2014) Inclusion complex of (-)-linalool and beta-cyclodextrin. J Therm Anal Calorim 115:2429–2437
Merkus FWHM, Verhoef JC, Marttin E, Romeijn SG, van der Kuy PHM, Hermens WAJJ, Schipper NGM (1999) Cyclodextrins in nasal drug delivery. Adv Drug Deliv Rev 36:41–57
Miller LA, Carrier RL, Ahmed I (2007) Practical considerations in development of solid dosage forms that contain cyclodextrins. J Pharm Sci 96:1691–1707
Miyazawa H, Ueda H, Nagase T, Endo T, Kobayashi S, Nagai T (1995) Physicochemical properties and inclusion complex formation of δ-cyclodextrin. Eur J Pharm Sci 3:153–162
Monbaliu J, van Beijsterveldt L, Meuldermans W, Szathmary S (1990) Disposition of hydroxypropyl β-cyclodextrin in experimental animals. In: 5th international symposium on cyclodextrins. de Santé, Paris, pp 514–517
Mora MM, Sánchez KH, Santana RV, Rojas AP, Ramírez HL, Torres-Labandeira JJ (2012) Partial purification and properties of cyclodextrin glycosiltransferase (CGTase) from alkalophilic Bacillus species. Springerplus 1:61
Mosher GL, Thompson DO (2002) Complexation and cyclodextrins. In: Swarbrick J, Boylan JC (eds) Encyclopedia of pharmaceutical technology, 2nd edn. Marcel Dekker, New York, pp 531–558
Munro IC, Newberne PM, Young RR, Bär A (2004) Safety assessment of γ-cyclodextrin. Regul Toxicol Pharmacol 39:S3–S13
Nieddu M, Rassu G, Boatto G, Bosi P, Trevisi P, Giunchedi P, Carta A, Gavini E (2014) Improvement of thymol properties by complexation with cyclodextrins: in vitro and in vivo studies. Carbohydr Polym 102:393–399
Nishikawa S, Nagata T, Morisaki I, Oka T, Ishida H (1996) Pathogenesis of drug-induced gingival overgrowth. A review of studies in the rat model. J Periodontol 67:463–471
Osterberg R, Demerlis C, Hobson D, Mcgovern T (2011) Trends in excipient safety evaluation. Int J Toxicol 30:600–610
Pilcer G, Amighi K (2010) Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm 392:1–19
Pinho E, Grootveld M, Soares G, Henriques M (2013) Cyclodextrin-based hydrogels toward improved wound dressings. Crit Rev Biotechnol Crit Rev B 1–10
Pinho E, Grootveld M, Soares G, Henriques M (2014) Cyclodextrins as encapsulation agents for plant bioactive compounds. Carbohydr Polym 101:121–135
Pitha J, Szente L, Szejtli J (1983) Molecular encapsulation of drugs by cyclodextrins and congeners. In: Bruck SD (ed) Controlled drug delivery, vol 1. CRC Press, Boca Raton, pp 125–148
Powell HM (1954) J Chem Soc 2658
Powell HM (1948) J Chem Soc 61
Prasad N, Strauss D, Reichart G (1999) Cyclodextrins inclusion for food, cosmetics and pharmaceuticals. European Patent 1084625
Pulley OA, French D (1961) Studies on the Schardinger dextrins. XI. The isolation of new Schardinger dextrins. Biochem Biophys Res Commun 5:11–15
Răileanu M, Todan L, Voicescu M, Ciuculescu C, Maria Maganu M (2013) A way for improving the stability of the essential oils in an environmental friendly formulation. Mater Sci Eng C 33:3281–3288
Ramalhete N, Afonso R, Almeida R, Cabral-Marques HM (2001) The effect of formulation variables on the aerosol performance of spray-dried insulin. In: 1st international pharmaceutical congress, 2nd Mediterranean conference on drug controlled release, 10th Panhellenic pharmaceutical congress. New perspectives in controlled release, Atenas
Rao VRS, Foster JF (1963) On the conformation of the D-glucopyranose ring in maltose and in higher polymers of D-glucose. J Phys Chem 67:951–952
Rekharsky MV, Inoue Y (1998) Complexation thermodynamics of cyclodextrins. Chem Rev 98:1875–1917
Rendleman JA Jr (1999) The production of cyclodextrins using CGTase from Bacillus macerans. In: Bucke C (ed) Carbohydrate biotechnology protocols, methods in biotechnology, vol 10. Humana Press, Totowa, pp 89–101
Reuscher H, Hinsenkorn R (1996) BETA W7 MCT-new ways in surface modification. J Incl Phenom Macrocycl Chem 25:191–196
Robyt JF (1998) Essentials of carbohydrate chemistry. Springer, Berlin
Romi R, Lo Nostro P, Bocci E, Ridi F, Baglioni P (2005) Bioengineering of a cellulosic fabric for insecticide delivery via grafted cyclodextrin. Biotechnol Prog 21:1724–1730
Rosso AM, Ferrarotti SA, Krymkiewicz N, Nudel BC (2002) Optimisation of batch culture conditions for cyclodextrin glucanotransferase production from Bacillus circulans DF 9R. Microb Cell Fact 3:1–9
Sá Couto A, Vieira J, Florindo HF, Videira MA, Cabral-Marques HM (2014) Characterisation of DM-β-cyclodextrin:prednisolone complexes and their formulation as eye drops. J Incl Phenom Macrocycl Chem. doi:10.1007/s10847-014-0420-8
Saenger W (1980) Cyclodextrin inclusion compounds in research and industry. Angew Chem Int Ed Engl 19:344–362
Saenger W (1982) Structure aspects of cyclodextrin inclusion compounds. In: Szejtli J (ed) Proceedings of I international symposium on cyclodextrins, Budapest, 1981. Reidel/Akadémiai Kiadó, Dordrecht/Budapest, pp 141–150
Saito Y, Tanemura I, Sato T, Ueda H (1999) Interaction of fragrance materials with 2-hydroxypropyl-beta-cyclodextrin by static and dynamic head-space methods. Int J Cosmet Sci 21:189–198
Salústio PJ, Pontes P, Conduto C, Sanches I, Carvalho C, Arrais J, Cabral-Marques HM (2011) Advanced technologies for oral controlled release: cyclodextrins for oral controlled release. AAPS PharmSciTech 12:1276–1292
Salústio PJ, Feio G, Figueirinhas J, Pinto J, Cabral-Marques HM (2009) The influence of the preparation methods on the inclusion of model drugs in a β-cyclodextrin cavity. Eur J Pharm Biopharm 71:377–386
Santos AL, Gouveia E, Cabral-Marques HM (2004) Cyclodextrins salicylic acid formulation for psoriasis treatment. In: Duchêne D (ed) Proceedings of the 12th international cyclodextrin symposium (Montpellier, France). Editions de Santé/APGI Publishing, Paris, pp 885–888
Sapkal N, Kilor V, Bhusari K, Daud (2007) Evaluation of some methods for preparing gliclazide- β-cyclodextrin inclusion complexes. Trop J Pharm Res 6:833–840
Schardinger F (1903a) Uber die Zulässigkeit des Warmhaltens von zum Gebuß bestimmten Nahrungsmittel mittelst Wärme speichernder Apparate, sog. Thermopore. Wien Klin Wochenschr 468–474
Schardinger F (1903b) Über Thermophile Bakterien aus verschiedenen Speisen und Milch, sowie über einige Umsetzungsprodukte derselben in kohlenhydrathaltigen Nährlösungen, darunter krystallisierte Polysaccharide (Dextrine) aus Stärke. Z Untersuch Nahr Genussm 6:865–880
Schardinger F (1904) Wien Klin Wochenschr 17:207–209
Schardinger F (1911) Bildung kristallisierter Polysaccharide (Dextrine) aus Stärkekleister durch Microben. Zentralbl Bakteriol Parasitenk Abt II 29:188–197
Shahrazi S, Saallah S, Mokhtar MN, Baharuddin AS, Md Yunos KF (2013) Dynamic mathematical modelling of reaction kinetics for cyclodextrins production from different starch sources using Bacillus macerans cyclodextrin glucanotransferase. Am J Biochem Biotechnol 9:195–205
Singh M, Sharma R, Banerjee UC (2002) Biotechnological applications of cyclodextrins. Biotechnol Adv 20:341–359
Singh R, Mishra S, Kumar N (2010) Optimization of α-amylase production on agriculture byproduct by Bacillus cereus MTCC 1305 using solid state fermentation. Res J Pharm Biol Chem Sci 1:867
Sivakumar N, Shakilabanu S (2013) Production of cyclodextrin glycosyltransferase by Bacillus megaterium. Int J Curr Microbiol App Sci 2:44–55
Slain D, Rogers PD, Cleary JD, Chapman SW (2001) Intravenous itraconazole. Ann Pharmacother 35:720–729
Sollogoub M (2013) Site-selective heterofunctionalization of cyclodextrins: discovery, development and use in catalysis. Synlett 24:2629–2640
Stella VJ, He Q (2008) Cyclodextrins. Toxicol Pathol 36:30–42
Stella VJ, Rajewski RA (1997) Cyclodextrins: their future in drug formulation and delivery. Pharm Res 14:556–557
Stevens DA (1999) Itraconazole in cyclodextrin solution. Pharmacotherapy 19:603–611
Sun DZ, Li L, Qiu XM, Liu F, Yin B-L (2006) Isothermal titration calorimetry and 1H NMR studies on host-guest interaction of paeonol and two of its isomers with β- cyclodextrin. Int J Pharm 316:7–13
Szathmary SC, Seiler K-U, Luhmann I, Huss H-J (1990) Pharmacokinetic behavior and absolute bioavailability of hydroxypropyl β-cyclodextrin after increasing dosing in volunteers. In: Duchéne D (ed) 5th international symposium on cyclodextrins. de Sante, Paris, pp 535–540
Szejtli J (1982) Cyclodextrin and their inclusion complexes. Akadémiai Kiadó, Budapest, pp 13 and 94–109
Szejtli J (1989) Downstream processing using cyclodextrins. Trends Biotechnol 7:171–174
Szejtli J (1998) Introduction and general overview of cyclodextrin chemistry. Chem Rev 98:1743–1753
Szejtli J (2004) Past, present, and future of cyclodextrin research. Pure Appl Chem 76:1825–1845
Szejtli J (2005) Cyclodextrin complexed generic drugs are generally not bio-equivalent with the reference products: therefore the increase in number of marketed drug/cyclodextrin formulations is so slow. J Incl Phenom Macro Chem 52:1–11
Szejtli J (1985) Molecular entrapment and release properties of drugs by cyclodextrins. In: Smolen, VF, Ball LA (Eds.), Controlled Drug Bioavailability, Vol. 3, Wiley, New York, pp. 365–420
Szejtli J (1988) Cyclodextrin technology. Kluwer, Dordrecht, p 450
Szente L, Fenyvesi E, Szejtli J (1999) Entrapment of iodine with cyclodextrins-potential application of cyclodextrins in nuclear waste management. Environ Sci Technol 24
WHO Technical Report Series (2002) Evaluation of certain food additives and contaminants, vol 909
Thombre RS, Kanekar PP (2013) Synthesis of β- cyclodextrin by cyclodextrin glycosyltransferase produced by Bacillus licheniformis MCM–B 1010. J Microbiol Biotech Res 3:57–60
Thompson DO (1997) Cyclodextrins-enabling excipients: their present and future use in pharmaceuticals. Crit Rev Ther Drug Carrier Syst 14:1–104
Tiwari G, Tiwari R, Rai AK (2010) Cyclodextrins in delivery systems: applications. J Pharm Bioallied Sci 2:72–79
Torres Marques M, Baptista AMJ, Cabral-Marques HM, Chitas IJ, Rodrigues de Carvalho M (1996) Método para aumentar a solubilidade e a estabilidade do cloranfenicol, através da formação de complexos de inclusão com ciclodextrinas, soluções contendo o referido complexo de inclusão e processo para separação dessas soluções. Portuguese Patent nr. 101
Totterman AM, Schipper NG, Thompson DO, Mannermaa JP (1997) Intestinal safety of water-soluble -cyclodextrins in paediatric oral solutions of spironolactone: effects on human intestinal epithelial Caco-2 cells. J Pharm Pharmacol 49:43–48
Ueda H, Ishii E, Motohama S, Endo T, Nagase H, Takaha T, Okada S (2000) Proceedings of the 10th international cyclodextrin symposium, Ann Arbor, 21–24 May
Uekama K (1981) In: Yakugaku Zasshi, p 857
Uekama K (2004) Design and evaluation of cyclodextrin-based drug formulation. Chem Pharm Bull 52:900–915
Uekama K, Otagiri M (1987) Cyclodextrins in drug carrier systems. In: Bruck SD (Ed.), Critical Reviews in Therapeutic Drug Carrier Systems, CRC Press, Boca Raton, 3:1–40
Uekama K, Hirayama F, Irie T (1998) Cyclodextrin drug carrier systems. Chem Rev 98:2045–2076
Urban M, Beran M, Adámek L, Drahorád J, Molík P, Matušová K (2012) Cyclodextrin production from amaranth starch by cyclodextrin glycosyltransferase produced by Paenibacillus macerans CCM 2012. Czech J Food Sci 30:15–20
Van Ommen B, De Bie AT, Bar A (2004) Disposition of 14C-α-cyclodextrin in germ-free and conventional rats. Regul Toxicol Pharmacol 39:57–66
Villiers A (1891) Sur la fermentation de la fécule par l’action du ferment butyrique. C R Acad Sci 112:536–538
Von Mach MA, BurhenneJ, Weilemann LS (2006) Accumulation of the solvent vehicle sulphobutyl β cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy. BMC Clin Pharmacol 6
Vozone C, Cabral-Marques HM (2002) Complexation of budesonide in cyclodextrins and particle aerodynamic characterization of its solid form for dry powder inhalation. J Incl Phenom 44:111–115
Waleczek K, Cabral-Marques HM, Hempel B, Schmidt P (2003) Phase solubility studies of pure (2)-α-bisabolol and camomile essential oil with β-cyclodextrin. Eur J Pharm Biopharm 55:247–251
Wang Z, Qi Q, Wang PG (2006) Engineering of cyclodextrin glucanotransferase on the cell surface of Saccharomyces cerevisiae for improved cyclodextrin production. Appl Env Microbiol 72:1873–1877
Wang K, Yan Y, Zhao G, Xu W, Dong K, You C, Zhanga L, Xing J (2014) In vitro and in vivo application of hydroxypropyl-β-cyclodextrin-grafted polyethylenimine used as a transdermal penetration enhancer. Polym Chem 5:4658–4669
Yano H, Kleinebudde P (2010) Improvement of dissolution behavior for poorly water-soluble drug by application of cyclodextrin in extrusion process: comparison between melt extrusion and wet extrusion. AAPS PharmSciTech 11:885–893
Yoshida A, Arima H, Uekama K, Pitha J (1988) Pharmaceutical evaluation of hydroxyalkyl ethers of b-cyclodextrins. Int J Pharm 46:217–222
Zhang J, Ma PX (2013) Cyclodextrin-based supramolecular systems for drug delivery: recent progress and future perspective. Adv Drug Deliv Rev 65:1215–1233
Zhao X, Courtney JM (2006) Surface modification of polymeric biomaterials: utilization of cyclodextrins for blood compatibility improvement. J Biomed Mater Res A 80:539–553
Zhekova BY, Stanchev VS (2011) Reaction conditions for maximal cyclodextrin production by cyclodextrin glucanotransferase from Bacillus megaterium. Pol J Microbiol 60:113–118
Zhou H, Goldman M, Wu J, Woestenborghs R, Hassell AE, Lee P, Baruch A, Pesco-Koplowitz L, Borum J, Wheat LJ (1998) A pharmacokinetic study of intravenous itraconazole followed by oral administration of itraconazole capsules in patients with advanced human immunodeficiency virus infection. J Clin Pharmacol 38:593–602
Zuo Z, Tam YK, Diakur J, Wiebe LT (2002) Hydroxypropyl-β-cyclodextrin-flutamide inclusion complex. II. Oral and intravenous pharmacokinetics of flutamide in the rat. J Pharm Sci 5:292–298
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this entry
Cite this entry
Sá Couto, A., Salústio, P., Cabral-Marques, H. (2015). Cyclodextrins. In: Ramawat, K., Mérillon, JM. (eds) Polysaccharides. Springer, Cham. https://doi.org/10.1007/978-3-319-16298-0_22
Download citation
DOI: https://doi.org/10.1007/978-3-319-16298-0_22
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-16297-3
Online ISBN: 978-3-319-16298-0
eBook Packages: Chemistry and Materials ScienceReference Module Physical and Materials ScienceReference Module Chemistry, Materials and Physics